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Virulence.
Vol.3, No.3, May 1, 2012.[Article in press]

Inhibition of bacterial superoxide defense: A new front in the struggle between host and pathogen.

Damo S, Chazin WJ, Skaar EP, Kehl-Fie TE.

Vanderbilt University School of Medicine; Nashville, TN USA; Department of Biochemistry and Chemistry, and Center for Structural Biology.

Abstract

Nutritional immunity is the name given to the sequestration of essential metals by vertebrates to limit growth of invading pathogens such as Staphylococcus aureus. While iron sequestration is the canonical example of nutritional immunity, recent work has highlighted the importance of manganese and zinc sequestration by vertebrates in controlling both bacterial and fungal infections. Our laboratories are investigating the biochemical basis for the sequestration of essential metals and the impact of this nutrient deprivation on the physiology of S. aureus and other pathogens. We have shown that during staphylococcal infection the manganese and zinc binding protein calprotectin (CP) is a critical component of nutritional immunity. Furthermore, this neutrophil protein is required to render the staphylococcal abscess devoid of manganese. However, the structural features responsible for binding these metals were unknown as was the impact of this CP-induced nutrient deprivation on S. aureus. In our recently published manuscript, we showed using isothermal titration calorimetry and mutagenesis experiments that CP contains two transition metal binding sites, and is capable of binding two zinc ions or one manganese ion with nanomolar affinity. Moreover, CP was found to reduce staphylococcal superoxide dismutase activity and other antioxidant defenses resulting in the accumulation of intracellular superoxide and increased sensitivity to oxidative stress. The inhibition of superoxide defenses by CP renders S. aureus more sensitive to neutrophil-mediated killing while animal modeling suggests that manganese sequestration by the host during infection reduces staphylococcal superoxide dismutase activity. In total, these results suggest a two hit model for the antimicrobial activity of CP whereby this protein both inhibits bacterial growth and renders microbial invaders more sensitive to other immune effectors.

 

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